Organ-specific eosinophilic disorders of the skin, lung, and gastrointestinal tract

doi:10.1016/j.jaci.2010.01.055

Journal of Allergy and Clinical Immunology

Volume 126, Issue 1, July 2010, Pages 3-13

https://doi.org/10.1016/j.jaci.2010.01.055 Get rights and content

Eosinophils are multifunctional leukocytes that increase in various tissues in patients with a variety of disorders. Locally, they can be involved in the initiation and propagation of diverse inflammatory responses. In this review the clinical association of eosinophils with diseases of the skin, lung, and gastrointestinal tract is summarized. An approach to determining the causal role of eosinophils in these diseases is presented. Recent findings concerning molecular diagnosis, cause, and treatment are discussed.

Section snippets

Cutaneous eosinophilia

Eosinophil infiltration is found in a broad spectrum of skin disorders (Table I).³ It is a characteristic feature of allergic diseases or parasitic infestations, but it is also observed in autoimmune diseases and hematologic diseases, as well as in association with tumors and bacterial or viral infections. Depending on the disease, eosinophils can be the predominant cell infiltrate, such as in eosinophilic cellulitis, or can be part of a mixed inflammatory infiltrate in the dermis, such as in

Lung eosinophilia

Eosinophils are relatively rare in normal lungs, and therefore they stand out both in tissue and airway lumen samples when present in increased numbers. A number of lung diseases are associated with blood and tissue eosinophilia (Table II). The extent to which eosinophils cause tissue damage in these diseases remains controversial, but most evidence points to them as being proinflammatory effector cells in noninfectious disorders, in which they are prominent. The most common association, at

Eosinophilic gastrointestinal disorders

Eosinophils are present throughout the healthy gastrointestinal tract, except for the esophagus, which typically contains no eosinophils.¹ Eosinophil-associated gastrointestinal disorders (EGIDs) are characterized by a high level of eosinophils within isolated or multiple segments of the gastrointestinal tract. Over the past decade, there has been a striking increase in the incidence of primary EGIDs, as well as a robust increase in data linking the development of EGIDs to atopy. The most

Summary

Eosinophilic tissue diseases are a heterogeneous group of diseases that include common conditions, such as asthma and AD; less common but regularly diagnosed diseases, such as EE; and rare diseases, such as eosinophilic pneumonia and CSS. The eosinophilia in these diseases might be associated with allergy to common aeroallergens but include rarer causes of eosinophilia, such as drug allergy and (in nonindustrialized countries) parasitic infection. However, in many patients with eosinophilic

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Eosinophilia can pose a diagnostic challenge for the clinician whether it is found incidentally, in the context of a drug reaction, or as part of evaluation for specific organ-associated signs or symptoms. Eosinophils have complex and multifaceted roles, which include but are not limited to immune regulation, inflammatory responses, and response to infections. Eosinophils are a subset of white blood cells with a short circulating half-life and are primarily considered tissue leukocytes. Although peripheral eosinophil counts of greater than 450–550 cells/µL are generally considered elevated, it is important to realize that tissue eosinophilia can be seen without peripheral eosinophilia. The degree of eosinophilia may serve as a guide to the differential diagnosis although does not usually help pinpoint the exact cause of eosinophilia. For instance, although mild eosinophilia may suggest atopic disease, more severe eosinophilia does not necessarily exclude those conditions. On the other hand, severe eosinophilia may suggest a myeloid neoplasm but could also be seen in the context of parasitic infestations, inflammatory responses, or drug reactions. Secondary etiologies of eosinophilia, such as allergies/atopy, drugs, and infections, should always be investigated, as treatment of these conditions generally results in symptom improvement. If evaluation for secondary causes of persistent eosinophilia is nonrevealing, workup for hypereosinophilic syndrome should be pursued. This heterogenous group of disorders includes several variants of which the two main ones are myeloproliferative and lymphocytic. The potential for organ damage should be continuously considered throughout evaluation and management of patients with eosinophilia as there is a broad spectrum of clinical manifestations associated with eosinophilia ranging from asymptomatic presentations to potentially fatal complications, such as persistent organ damage, thromboembolism, and malignant transformations.
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Basophils are important effector cells in allergic disorders and anti-parasitic immune response. A number of activators including interleukin 3 (IL-3) and IgE have been identified in the regulation of human basophils expressing mediators such as histamine and leukotriene C4 (LTC4) and cytokines, including IL-4 and IL-13. Human basophils express high levels of IL-2 receptors. However, the function of the IL-2 pathway in basophils remains unknown. Here, we identified that IL-2 induced the activation of human basophils in vitro to express a variety of inflammatory cytokines and chemokines including IL-5, IL-13, GM-CSF and CCL-17. This effect by IL-2 is confirmed by an upstream regulator analysis using Ingenuity pathway analysis. Of note, one of the top regulated cytokines, IL-5, was for the first time identified to be induced by IL-2 in human basophils rather than IL-3 or anti-IgE. Immunofluorescence analysis of skin specimens from bullous pemphigoid and eczema revealed that infiltrating basophils in skin lesions widely expressed IL-5 and GM-CSF. Together, our findings reveal IL-2 as a novel regulator of human basophils. This adds a new layer to support the importance of basophils in allergic disorders.
The targeted eosinophil-lowering effects of dexpramipexole in clinical studies
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Dexpramipexole, an orally bioavailable small molecule previously under clinical development in amyotrophic lateral sclerosis, was observed during routine safety hematology monitoring to demonstrate pronounced, dose- and time-dependent eosinophil-lowering effects, with minor reductions on other leukocyte counts. Analysis of hematology lab values across two double-blind, randomized placebo-controlled clinical trials at total daily doses ranging from 50 mg to 300 mg demonstrated that dexpramipexole consistently and markedly lowered peripheral blood eosinophils. This effect developed after 1 month on treatment, required 3–4 months to reach its maximum, remained constant throughout treatment, and partially recovered to baseline levels upon drug withdrawal. All doses tested were well tolerated. The overall adverse event rate was similar for dexpramipexole and placebo, and notably with no increase in infection-related adverse events associated with eosinophil-lowering effects. Given the reliance on and insufficiency of off-label chronic corticosteroid therapy for hypereosinophilic syndromes and other eosinophilic-associated diseases (EADs), a need exists for less toxic, more effective, targeted therapeutic alternatives. Further clinical studies are underway to assess the eosinophil-lowering effect of dexpramipexole in the peripheral blood and target tissues of EAD patients and whether such reductions, if observed, produce clinically important benefits.
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A series of novel chromen-4-one analogs 9a-d and 10a-u was designed, synthesized and evaluated for their IL-5 inhibitory activity. Most of the chromen-4-one analogs showed strong inhibitory activity in low micro molar potency. Among them, 5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-2-isopropyl-4H-chromen-4-one (10t, 90.0% inhibition at 30 μM, IC₅₀ = 5.5 μM, CLogP = 4.76887) and 2-cyclohexyl-5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-4H-chromen-4-one (10u, 95.5% inhibition at 30 μM, IC₅₀ = 3.0 μM, CLogP = 5.96187) showed the best inhibition. The structure activity relationship reveals that the hydrophobic cyclohexylmethoxy group at the position 5 of the chromen-4-one ring A is preferable than at position 6 and the dual hydrogen bonding acceptor property on the chromen-4-one ring should be important for the inhibitory activity. In addition, the optimum length of the side chain at position 3 of chromen-4-one ring is critical for the donation of hydrogen to the binding site and the 3-hydroxypropoxy group showed the best activity. Moreover, the conformational restrictor (isopropyl, cyclohexyl group) at position 2 is much more favorable for the formation of effective conformer of side chain with hydrogen bonding donor property of these chromen-4-one analogs.
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Citation Excerpt :
The abundant granules of eosinophils contain a battery of highly toxic proteins including major basic proteins (MBP) 1 & 2, eosinophil peroxidase (Epx), eosinophil cationic protein, and eosinophil-derived neurotoxin (Hogan et al., 2008). Upon release from granules, these proteins are toxic not only to bacterial, viral, and helminth pathogens but also to host cells and tissues (Furuta et al., 2005; Lee et al., 2004; Simon et al., 2010). Several studies link granule proteins to human eosinophil-linked diseases that affect the airways and esophagus.
Eosinophils are now recognized as multifunctional leukocytes that provide critical homeostatic signals to maintain other immune cells and aid tissue repair. Paradoxically, eosinophils also express an armory of granule-localized toxins and hydrolases believed to contribute to pathology in inflammatory disease. How eosinophils deliver their supporting functions while avoiding self-inflicted injury is poorly understood. We have demonstrated that cystatin F (CF) is a critical survival factor for eosinophils. Eosinophils from CF null mice had reduced lifespan, reduced granularity, and disturbed granule morphology. In vitro, cysteine protease inhibitors restored granularity, demonstrating that control of cysteine protease activity by CF is critical for normal eosinophil development. CF null mice showed reduced pulmonary pathology in a model of allergic lung inflammation but also reduced ability to combat infection by the nematode Brugia malayi. These data identify CF as a “cytoprotectant” that promotes eosinophil survival and function by ensuring granule integrity.

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: Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

: Supported in part by the National Institutes of Health National Institute of Allergy and Infectious Diseases, the Food Allergy and Anaphylaxis Network, the Food Allergy Project, the CURED Foundation, and the Buckeye Foundation (to M. E. R.).

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Reviews and feature articleOrgan-specific eosinophilic disorders of the skin, lung, and gastrointestinal tract

Section snippets

Cutaneous eosinophilia

Lung eosinophilia

Eosinophilic gastrointestinal disorders

Summary

J Allergy Clin Immunol

J Allergy Clin Immunol

J Invest Dermatol

J Allergy Clin Immunol

Blood

J Invest Dermatol

J Invest Dermatol

J Allergy Clin Immunol

Blood

J Am Acad Dermatol

J Allergy Clin Immunol

Adv Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Curr Opin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Lancet

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunol Allergy Clin North Am

Lancet

Gastroenterology

J Allergy Clin Immunol

Gastrointest Endosc Clin North Am

J Allergy Clin Immunol

J Allergy Clin Immunol

Gastroenterology

Gastroenterology

J Allergy Clin Immunol

Gastrointest Endosc Clin North Am

J Allergy Clin Immunol

J Allergy Clin Immunol

Gastrointest Endosc Clin North Am

Gastroenterology

Hum Pathol

The eosinophil

Annu Rev Immunol

A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

N Engl J Med

Differential cytokine profiles in peripheral blood lymphocyte supernatants and skin biopsies from patients with different forms of atopic dermatitis, psoriasis and normal individuals

Int Arch Allergy Immunol

Eosinophil activation and in situ interleukin-5 production by mononuclear cells in skin lesions of patients with drug hypersensitivity

J Dermatol

Characterization of skin cytokines in bullous pemphigoid and pemphigus vulgaris

Br J Dermatol

Analysis of leukemia inhibitory factor, type 1 and type 2 cytokine production in patients with eosinophilic fasciitis

J Rheumatol

Role of Th2 cytokines, RANTES and eotaxin in AIDS-associated eosinophilic folliculitis

Acta Derm Venereol

Wells' syndrome: a pathogenic role for circulating CD4+CD7- T cells expressing interleukin-5 mRNA

Br J Dermatol

Reviews and feature article
Organ-specific eosinophilic disorders of the skin, lung, and gastrointestinal tract